Cycle length: Every 21 days.
Duration of therapy: Maximum of four cycles, followed by maintenance therapy with pembrolizumab alone every three weeks.* |
| Drug | Dose and route | Administration | Given on days |
| Pembrolizumab | 200 mg | Dilute in NS or D5W¶ to a final concentration between 1 to 10 mg/mL and infuse over 30 minutes through an 0.2- to 5-micron sterile, nonpyrogenic, low-protein-binding inline or add-on filter. | Day 1 |
| PaclitaxelΔ | 200 mg/m2 IV | Dilute in NS or D5W¶ to a final concentration of 0.3 to 1.2 mg/mL and administer over one to three hours via 0.22 micron in-line filter; use non-PVC container and tubing set. | Day 1 |
| Carboplatin | AUC◊ = 6 mg/mL per min IV | Dilute in 250 mL NS or D5W¶ and administer over 30 minutes. | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE; (MINIMAL with pembrolizumab monotherapy).§
- Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".
|
| Immune status | - Anti-PD-1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. There are only limited data on the safety and efficacy of checkpoint inhibitors such as pembrolizumab in patients with an underlying autoimmune disorder. Pembrolizumab should be used with extreme caution in such individuals.
|
| Prophylaxis for infusion reactions | - Premedicate with dexamethasone plus both an H1 and an H2 receptor antagonist prior to paclitaxel administration. There is no standard premedication for pembrolizumab.
- Refer to UpToDate topic on "Infusion reactions to systemic chemotherapy".
|
| Vesicant/irritant properties | - Paclitaxel can cause significant tissue damage; avoid extravasation. Carboplatin is an irritant.
- Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-antineoplastic vesicants".
|
| Infection prophylaxis | - The incidence of grade 3 through 5 neutropenia was approximately 15% in the pembrolizumab-plus-chemotherapy arm versus 17% in the chemotherapy-only arm.[1] The decision to use primary prophylaxis with a hematopoietic growth factor should be individualized according to existing guidelines.
- Refer to UpToDate topic on "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".
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| Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) every one to two cycles.
|
| Regulatory issues | - An FDA-approved patient medication guide, which is available with the US Prescribing Information,[2] must be dispensed with pembrolizumab.
|
| Monitoring parameters: |
- CBC with differential and platelet count before each treatment.
|
- Assess electrolytes (including glucose), liver, and renal tests every three weeks prior to each new cycle of treatment. Thyroid function prior to initiation of therapy and every one to two cycles during treatment, and/or as clinically indicated.
|
- Assess changes in neurologic function prior to each treatment cycle.
|
- Monitor for infusion reactions, fatigue, colitis, hepatotoxicity, hypophysitis, adrenal insufficiency, hypo- or hyperthyroidism, nephrotoxicity, pneumonitis, hyperglycemia, and skin rash. Many other clinically relevant immune-mediated toxicities have been observed, which may involve any organ system or tissue, and may be severe or fatal.
- While immune-mediated toxicities generally occur during treatment with pembrolizumab, adverse reactions, including infusion-related reactions, may also develop weeks to months after therapy discontinuation.
- Refer to UpToDate topic on "Toxicities associated with checkpoint inhibitor immunotherapy".
|
| Suggested dose modifications for toxicity:¥ |
| Myelotoxicity | - During the initial phase of combined therapy, treatment with pembrolizumab, paclitaxel, and carboplatin should be delayed until the ANC is >1500/microL and platelet count is >100,000/microL.[3,4] If a patient developed febrile neutropenia during the prior course, then the paclitaxel and carboplatin doses should be reduced by 20 to 25% for subsequent courses.[5] An alternative to dose reduction is the institution of hematopoietic growth factor support. The carboplatin dose should be decreased by 25% in patients whose platelet count nadir is <50,000/microL of whose neutrophil nadir is <500.[4]
- Consider discontinuing paclitaxel and carboplatin therapy if a patient qualifies for a third dose reduction. Dose reductions should be maintained for subsequent cycles.[1]
|
| Renal/hepatic toxicity | - Alterations in renal function during therapy may require a recalculation of the carboplatin dose.
- Paclitaxel dose may need to be adjusted for hepatic impairment on day 1 of each cycle.
- Refer to UpToDate topics on "Dosing of anticancer agents in adults" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents".
|
| Neurotoxicity¥ | - For patients who develop severe neuropathy (grade 3 or 4) for a week or longer, the dose of paclitaxel should be reduced by 20% for subsequent courses.[3]
|
| Pembrolizumab immune-related toxicity | - No dosage reductions of pembrolizumab are recommended; treatment is withheld or discontinued to manage toxicities.[1,2,6]
- All patients should be closely monitored and evaluated for immune-mediated adverse effects at least every three weeks during therapy.
- In general, if an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes. Based on the type and severity of the reaction, withhold treatment and administer systemic glucocorticoids. Upon resolution to ≤grade 1, initiate glucocorticoid taper. Immune-mediated adverse reactions that do not resolve with systemic glucocorticoids may be managed with other systemic immunosuppressants (based on limited data). Discontinue pembrolizumab permanently for any grade 4 or recurrent grade 3 immune-mediated adverse event or one that is life threatening, grade 3 pneumonitis, AST/ALT elevation >8 times ULN, total bilirubin elevation >3 times ULN in patients with no hepatic tumor involvement, AST/ALT elevation to >10 times ULN for hepatitis with hepatic tumor involvement, grade ≥2 myocarditis, grade 3 neurologic toxicity, suspected exfoliative dermatologic condition, severe (grade 3) or life-threatening (grade 4) infusion reactions, or if there is an inability to reduce glucocorticoid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating glucocorticoids.[2]
- Guidelines for managing specific toxicities, including immune-mediated adverse events, are available in the United States Prescribing Information for pembrolizumab,[2] from ASCO,[6] from the MASCC,[7] from the NCCN,[8] and from the SITC.[9]
- Refer to UpToDate topic on "Toxicities associated with checkpoint inhibitor immunotherapy".
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
